Inhalation devices

ABSTRACT

The present invention provides devices for the oral or nasal inhalation of finely divided materials such as medicinal agents and drugs.

This is a continuation of application Ser. No. 07/738,924 filed on Aug.1, 1991, now U.S. Pat. No. 5,337,740.

BACKGROUND OF THE INVENTION

This invention relates to devices for the oral or nasal inhalation offinely divided materials, such as medicinal agents and drugs.

Certain diseases of the respiratory tract are known to respond totreatment by the direct application of medicinal agents. As many suchagents are most readily available as a finely divided material, e.g., indry powdered form, their delivery is most conveniently accomplished byinhaling the finely divided material through the nose or mouth. Thisresults in better utilization of the medicinal agent in that it isdeposited exactly at the site desired and where its action may berequired; hence, very minute doses of the therapeutic agent are oftenequally as efficacious as larger doses administered by other means, witha consequent marked reduction in the incidence of undesired sideeffects. Alternatively, the therapeutic agent in this form may be usedfor treatment of diseases other than those of the respiratory system.When the drug is deposited on the very large surface areas of therespiratory tract, it may be very rapidly absorbed into the bloodstream; hence, this method of application may take the place ofadministration by injection, tablet, or other conventional means.

A variety of inhalation devices for the delivery of finely dividedmaterials are known in the art. For example, U.S. Pat. No. 4,240,418discloses inhalation devices wherein a container of finely dividedmaterial is positioned so that the material from the container can passby gravity to a delivery area of the device from which it is dispensed.Accordingly, these devices suffer the disadvantage that the user mustmaintain the device in a particular position so that the finely dividedmaterial can pass by gravity to the collecting plate and is notdislodged therefrom prior to dispensing. It appears that such devicesalso require a large dispensing passage to prevent interference with thefree fall of a relatively large load of the finely divided material.

Other known inhalation devices incorporate a deflector (U.S. Pat. No.4,098,273) or a hollow tube (U.S. Pat. No. 3,938,516) to divert air flowinto a chamber to dislodge the finely divided material, therebyrequiring a substantial flow of air to disperse the finely dividedmaterial. Inhalation sufficient to create such a substantial flow of airis difficult for some users, e.g., asthmatics. Furthermore, it isbelieved that such devices deliver somewhat imprecise doses due to theinevitable variations in residue of finely divided material left behindin the container after dispensing.

Some known inhalation devices use members which vibrate to dispense thefinely divided material, thus increasing the complexity and bulk of thedevice. For example, the devices of U.S. Pat. No. 3,948,264, utilizebatteries to activate vibrators. Other devices incorporate breathactivated vibratable members to disperse the finely divided materials.See, e.g., U.S. Pat. Nos. 3,888,253 and 4,995,385 which include a memberwhich vibrates in the airflow to dispense the finely divided material.Still other known devices use a breath activated propeller device tospin the container of finely divided material, thereby casting thematerial out by centrifugal force, e.g., U.S. Pat. No. 3,507,277. Arelatively high velocity of air flow is required to activate suchdevices, again a problem for breath impaired users.

Moisture in most powders tends to cause agglomeration and clumpingthereby inhibiting the breakup and dispersion of the finely dividedmedication, an essential step in effective dispensing of the material.However, the manner in which many known devices operate renders hermeticsealing of the container of finely divided material impossible. In stillother known devices, the containers for finely divided materials aregelatin capsules which are susceptible to atmospheric moisture.

In some known inhalation devices, e.g., conventional aerosolbronchodilators, drug delivery is achieved by the sometimes difficultcoordination of digital force with voluntary inhalation.

New and more potent drugs which can be used in increasingly smallquantities are being developed on an ongoing basis. In most instances,known inhalation devices for finely divided materials are not capable ofdelivering such small quantities without the addition of a significantamount of filler. It is highly desirable to minimize the use of suchfillers, e.g., in order to reduce the likelihood of side effects.

It can be seen that presently known devices for the delivery of finelydivided materials suffer disadvantages which include imprecise delivery,inability to deliver directly from a hermetically sealed container, highbreath demands upon the user, limited portability due to bulk, andcomplexity of design. Thus, alternative inhalation devices are beingsought.

SUMMARY OF THE INVENTION

Devices of the present invention utilize air flow through a container offinely divided material, the container having one section open to theatmosphere and another open to the interior of the device, to dispensethe finely divided material. As air is drawn through the container andthe device by oral or nasal inhalation of the user, increased airvelocity causes decreased pressure within the device. This results in apressure differential between the section of the container open to theatmosphere and the section open to the body member. The resultant flowof air from outside atmospheric pressure to inside partial vacuum picksup the finely divided material carrying it into the device to mix withthe internal flow of air. The passage of air through the container offinely divided material, and the device virtually purges the materialfrom both the container and the device, thereby carrying it along withthe user's inspired breath to the lungs or nasal passages.

The inhalation devices of the present invention overcome many of thedisadvantages associated with known devices. One important advantageresides in their ability to accurately and repeatedly disperse thefinely divided material. Because it is air flow through the finelydivided material that causes dispensing, the air flow through thecontainer typically causes virtually all of the finely divided materialto be evacuated. Another advantage of devices in accordance with thepresent invention is that loads of finely divided material as low asabout 0.1 mg can be dispensed. This is also an important advantagebecause by dispensing small doses of finely divided materials, such aspharmaceuticals, the use of fillers, such as lactose, is minimized.

Yet another major advantage of inhalation devices in accordance with thepresent invention is the total protection of the finely divided materialup to the moment of use. Each individual dose is hermetically sealed, insome cases removably hermetically sealed, to assure as long a shelf lifeas possible and freedom from contamination.

Furthermore, the present inhalation devices require little or nocoordination on the part of the user, since inhalation of breath causesthe device to function. In one embodiment, the user need only press downon a conveniently located button to perforate the container of finelydivided material to ready the device for use. The finely dividedmaterial remains in the container until activated by patient inhalationwhich can occur within any reasonable time period after the containerseal is broken. Moreover, a relatively low velocity of air flow throughthe body member, as measured by a standard flow meter, is adequate toachieve full dispensing, generally even for a child.

The inhalation devices of the present invention have the furtheradvantage of great simplicity which renders them capable of being madein a small size for inconspicuous portability, further enhancing thedesirability for use as a personal dispenser. One preferred inhalationdevice of the present invention is pen-like in design to render it easyto use inconspicuosly, as well as to provide other important advantages.

The devices disclosed herein are adapted for receiving from a single tomultiple containers of finely divided material. In one preferredembodiment, the device is adapted to receive a circular disk containingmultiple containers of finely divided material. Not only does thisembodiment provide a convenience for the user, it also provides aneconomy in production filling.

One inhalation device in accordance with the present invention comprises(i) a body member having an air passageway therethrough, one end of thebody member being adapted for insertion into the mouth or nose of theuser; (ii) a holder connected to the body member for receiving at leastone removably sealed container of finely divided material; and (iii) atleast one piercer for piercing the removably sealed container while thesealed container is in the holder, the piercer extending from the bodymember and into the holder and having a passageway therethrough open tothe body member and the holder. A removably sealed container is placedin the holder thereby causing the piercer to pierce the sealedcontainer. The removable seal is then removed and air drawn through theunsealed and pierced container, the piercer, and the body membercooperate to cause finely divided material disposed in the container tobe dispensed therefrom.

In another similar embodiment of the present invention, the piercerextends from the body member through the holder for a distance greaterthan the dimension of the sealed container to be pierced, thus,providing devices for the oral or nasal inhalation of finely dividedmaterials from a sealed container which need not be provided with aremovable seal. In such embodiments, the dimensions of the piercer aresuch that when the sealed container is placed in the holder therebycausing the piercer to pierce through the sealed container therein, thefinely divided material is transferred from the container to the airpassageway of the piercer as it passes through the container.Subsequently, air drawn through the piercer and the air passageway ofthe body member cooperate to cause the finely divided material disposedin the piercer to be dispensed therefrom.

The present invention provides yet another inhalation device fordispensing finely divided materials from a sealed container which is notprovided with a removable seal. Such devices typically include at leasttwo piercers and comprise: (i) a body member having an air passagetherethrough, one end of the body member being adapted for insertioninto the mouth or nose of the user; (ii) a holder for receiving at leastone sealed container of finely divided material, the holder beingconnected to the body member; (iii) at least one first piercer forpiercing the sealed container while in the holder, the first piercerextending into the interior of the holder and having an air passagewaytherethrough open to the body member and the holder; (iv) at least onesecond piercer for piercing the sealed container while in the holder,the second piercer extending into the holder and having a air passagewaytherethrough, open to the interior and exterior of the holder; and (v)engaging means for causing the first and second piercer, while thesealed container is in the holder, to pierce the sealed container.

These devices operate so that when the sealed container is positioned inthe holder and the engaging means causes the first and second piercersto pierce the sealed container to create an air passageway therethrough,air drawn through the first piercer, the pierced container, the secondpiercer, and the passageway of the body member cooperate to cause finelydivided material disposed in the pierced container to be dispensedtherefrom.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings:

FIG. 1 is an perspective view of one embodiment of a device inaccordance with the present invention.

FIG. 2 is an perspective view of another embodiment of a deviceaccording to the present invention.

FIG. 3A is a section on line 3A-3A of the device shown in FIG. 1,showing a cross-section of a container of finely divided materialdisposed therein, wherein the removable seal has been removed.

FIG. 3B is an end view of the device shown in FIG. 1.

FIG. 3C is a plan view of the device shown in FIG. 1.

FIG. 4 is cross-sectional view of yet another embodiment of a device ofthe present invention, similar to that shown in FIG. 3.

FIG. 5 is an enlarged cross-sectional view of the removably sealedcontainer of finely divided material shown in FIG. 3A wherein theremovable seal is intact.

FIG. 6A is a cross-sectional view of the device shown in FIG. 2 takenalong line 6A--6A of FIG. 2A.

FIG. 6B is an end view of the device shown in FIG. 2 showing theinhalation end.

FIG. 6C is an end view of the device shown in FIG. 2 showing the airintake end.

FIG. 6D is a plan view of the device shown in FIG. 2.

FIG. 7A is a plan view of a disk provided with multiple sealedcontainers containing finely divided materials for use in the presentinvention.

FIG. 7B is a side view of the disk shown in FIG. 7A.

FIG. 7C is a bottom view of the disk shown in FIG. 7A.

FIG. 8 is a cross-sectional view of another device in accordance withthe present invention, showing a cross-sectional view of a taperedcontainer.

FIGS. 9A-9D are cross-sectional views of yet other devices in accordancewith the present invention.

FIG. 10 is a graph showing total excretion of free H³ -cortisol for a 24hour period after administration nasally in accordance with the presentinvention as compared with excretion of free H³ cortisol afterconventional oral administration.

FIG. 11 is a graph showing excretion of free H³ -cortisol over a 24 hourperiod after administration nasally in accordance with the presentinvention as compared with excretion of free H³ cortisol afterconventional oral administration.

DETAILED DESCRIPTION OF THE INVENTION

Although the inhalation devices of the present invention are primarilyillustrated by means of devices which have been adapted for oralinhalation, it will be appreciated by those skilled in the art that suchdevices may also be adapted for nasal inhalation of finely dividedmaterials.

Referring now to FIGS. 1 and 3 there is shown one embodiment of aninhalation device of the present invention for the oral inhalation offinely divided materials from a removably sealed container. The deviceshown comprises a body member 20 having an air passageway 22therethrough, the air passageway comprising a venturi. One end 24 of thebody member 20 is adapted for insertion into the mouth of the user. Theother end 27 is an air intake end and may optionally be provided with ascreen (not shown) to filter inhaled air. A holder 40, comprising anopen receptacle for receiving at least one removably sealed container 60of finely divided material 64, is connected to body member 20. At leastone piercer 26 (shown in FIG. 3A) for piercing the removably sealedcontainer 60, while the sealed container 60 is in the holder 40, extendsfrom the body member 20 and into the holder 40. The piercer 26 has apassageway therethrough open to the body member 20 and the holder 40.

The container 60 is dimensioned to extend above the holder 40 whilepresent therein so that the user can access the removable seal 62 andcan grasp and remove the container 60 after use. An enlargedcross-sectional view of a removably sealed container is shown in in FIG.5. In use, the removably sealed container 60 is placed in the holder 40thereby causing the piercer 26 to pierce the sealed container 60 and tohold the tab of sealing material 66 created thereby (See, e.g., FIG. 5)against the container 40. The removable container seal 62 is thenremoved, thereby creating an opening to the atmosphere.

The device shown in FIG. 4 is similar to that shown in FIG. 3. However,it is adapted for use in conjunction with a sealed container which isnot provided with a removable seal. The piercer 26 in this deviceextends from the body member 20 through the holder 40 for a distancegreater than the dimension of the sealed container 60 to be pierced.When the sealed container 60, is placed in the holder 40 as shown inFIG. 4, thereby causing the piercer 26 to pierce through the sealedcontainer 60, the finely divided material 64 is transferred from thecontainer 60 to the air passageway of the piercer 26 from which it isdispensed upon inhalation by the user.

In use, the mouthpiece 24 of the inhalation devices of the presentinvention is placed inside the lips of the user to minimize impingementof the finely divided material on the mouth. A quick intake of breathcauses air to flow through the air intake end 27 and into air passageway22 of body member 20 to create a partial vacuum, thereby causing thefinely divided material 64 to be dispersed from (i) the pierced andunsealed container 60 in the embodiment showing in FIGS. 1,3, and 9; and(ii) from the air passageway of the piercer 26 in the embodiment shownin FIG. 4.

Another preferred device in accordance with the present invention, shownin FIGS. 2 and 6, comprises a body member 20 having an air passageway 22therethrough, and a holder 40. One end 24 of the body member 20 isadapted for insertion into the mouth of the user. The other end 27, theair intake end, of body member 20 is provided with a screen 28 tominimize inhalation of undesired materials, e.g., dust, which may bepresent in the air. A first piercer 26 for piercing the sealed container60 while in the holder 40, extends into the interior of the holder 40and has a passageway therethrough open to the body member 20 and theholder 40.

In the embodiment shown in FIGS. 2 and 6, the holder 40 is adapted toreceive a disk 70 provided with multiple containers 60 as shown in FIG.7. The holder 40 comprises a receptacle 42 fixed to the body member 20and a cover 44 movably attached to receptacle 42 by hinge means 46. Thedisk 70 while in the holder 40 is rotably, centrally disposed on a pin(not shown) which is mounted therein.

The disk 70 is provided with a conventional locking means so that duringrotation, the disk is locked in position each time a container of finelydivided material is disposed adjacent piercers 26, 52, thereby locatingeach single dose container 60 for dispensation. Disks of a givendiameter can contain different numbers of single doses depending uponthe requirements of the particular drug in use. Thus, one inhalationdevice in accordance with the present invention can have many differentdrug applications.

A preferred multiple cavity disk 70 is about 0.75 to 1.25 inches indiameter, about 0.250 to 0.312 inches deep and is provided withindividual sealed containers, similar to those shown in FIG. 5. The disk70 is typically made of conventional molded plastics, such as,polypropylene, polyethylene, acetal, ABS and so forth. However, otherconventional materials known to those skilled in the art may also beused. Although disk 70 can be rotated mechanically after use, forsimplicity the preferred method is hard rotation. It will be apparent tothose skilled in the art that the disk 70 could be replaced withmultiple container strips, either rigid or in flexible rolls, e.g., asin cartridge belt for an automatic weapon, and so forth.

The cover 44 is provided with perforations 45 to provide an opening tothe atmosphere through which air is drawn upon inhalation by the userwhen the pierced container 60 is in the device. The cover is alsoprovided with a section 48 having a first leaf spring 50. Section 48 ismovably mounted in the cover 44, flanges 49 providing stops to maintainsection 48 in cover 44, when cover 44 is raised to insert a disk 70 ofsealed containers 60.

A second piercer 52 mounted in cover section 48 extends into theinterior of the holder 40 and has a passageway therethrough open at bothends to the holder 40. The second piercer 52 is positioned relative tothe first piercer 26 so that they are capable of cooperating to piercethe sealed container 60 when the sealed container 60 is in receptacle 42and rotated into dispersing position adjacent piercers 26, 50.

Receptacle 42 is provided with a second leaf spring 51 disposed betweenbody member 20 and disk 70, when the disk 70 is in holder 40. Themovable cover section 48 cooperates with leaf springs 50, 51 to providethe engaging means for causing the first and second piercers 26, 52 topierce the sealed container 60 while in the holder 40 when movable coversection 48 is pressed towards container 60 by the user.

To operate the device shown in FIGS. 2 and 6, the movable cover section48 is depressed by the user so that piercers 26 and 52 pierce the seals61 (shown in FIG. 5) of the container 60 of finely divided material 64,thereby creating an air passage. The air passage is blocked only by thefinely divided material 64, because the tab of pierced seal 66 is heldagainst the side of holder 40 by piercer 26 (See FIG. 5). The movablecover section 48 is held in a depressed position until after inhalationby the user so that the piercers 52, 26 will remain in contact with thecontainer 60 of finely divided material 64. The passage of air throughthe perforation in seal 62, needle 52, container 60, needle 26, and airpassageway 22, virtually purges the finely divided material 64 from thecontainer 60, carrying it along with the patients inspired breath intothe lungs.

In preferred embodiments of the present invention, the air passageway 22of the body member 20 comprises a venturi or a tube, wherein the firstpiercer 26 is disposed at or adjacent the smallest diameter of theventuri or the midpoint of the tube. A venturi is a particularlypreferred configuration for the air passageway 22 of the body member asshown, e.g., in FIGS. 3A, 4, 6A and 8.

In one particularly preferred embodiment of the present invention, thebody member 20 has a major diameter at each end ("B" in FIG. 6A) about0.3 to 0.8 inches with, in the case of embodiments wherein the airpassageway 22 composes a venturi, a minor diameter ("A" in FIG. 6A) atthe venturi's point of restriction 23 of about 0.2 to 0.5 inches. Thesedimensions are based upon end 24 of body member 20 being adapted forinsertion into the nose or mouth of the user, as well as providing aminor diameter adequately large to allow an uninhibited intake ofbreath. The inner diameter ("D" in FIG. 6A) of holder 40 is dimensionedto receive disk 70 and may be from about 0.5 to 1.5 inches when A and Bhave the dimensions set forth above. It is understood that thecircumstances of use will dictate the dimensions without altering theintent of the device. For example, one might wish the unit to resemble apocketable pen as shown in FIG. 8 to achieve an enhanced degree ofportability.

The relative dimensions of the containers of finely divided material foruse in the devices of the present invention and the piercer(s) of suchdevices are selected to provide accurate delivery of the finely dividedmaterial. The dimensions of the piercer 26 which opens to body member20, as well as the end or ends of the container 60 pierced thereby, areselected to minimize entrapment of the finely divided material 64adjacent piercer 26. Finely divided material below the orifice of theneedle 26 is unlikely to evacuate, yet the needle 26 must project highenough to hold tab 66 (shown in FIG. 5) in a vertical position. If tab66 is not held parallel to the sides of the container, it may be drawndown by the vacuum created upon inhalation to seal off piercer 26,thereby upsetting dosage accuracy.

In some preferred embodiments of the present invention, the diameter ofthe cylindrical container is stepped down at the end disposed adjacentpiercer 26 while in the device, to minimize entrapment of the finelydivided material. See, e.g., stepped down section 69 in FIG. 5. The stepis preferably equal in length to the outside diameter of piercer 26(i.e., about the size of tab 66 in the vertical position). Thedimensions of piercer 52 are not as important since the tab created bypiercer 52 is not positioned so that it will interfere with dispensingof the finely divided material. However, piercer 52 must be sufficientlylarge to permit unobstructed flow of air.

The inhalation devices of the present invention shown in the figuresembody a piercer 26 which comprises a needle, preferably sharpened atthe piercing end to about a 30° to 45° angle. The rim of the needleopposite the apex of the needle point is typically blunted to avoidcutting a piece of the seal 61 of container 60 free. As shown in FIG. 5,this leaves a tab 66 of the seal "hinged" to the container 60 therebypreventing ingestion.

In a preferred embodiment the needle 26 has an inner diameter of about0.01 to 0.15 inches and an outer diameter of about 0.03 to 0.170 inches.Such inside diameters afford adequate flow of finely divided materialwhile still retaining it in the container 40 until the moment ofdischarge. However, diameters outside the preferred ranges may beuseful, depending in part upon the fluidity of the finely dividedmaterial. For example, a highly fluid finely divided material would callfor a smaller diameter needle 26 than less fluid material in order tohold the powder inside the container 40 until evacuated by theinhalation of the user.

In preferred embodiments of the present invention, other than thosesimilar to the embodiment shown in FIG. 4, the needle 26 extends intothe container 60 for approximately one needle diameter length, plus thelength of the sharpened angle, or sufficiently far to hold tab 66 in aposition generally parallel to the side of the needle 26 and adjacentthe inner wall of the container 40, thereby leaving a clear passage forair flow. This enables tab 66 to remain attached to the container 40 andto be bent to a position as shown in FIG. 5.

In embodiments wherein the needle 26 preferably has an inner diameter ofabout 0.01 to 0.15 inches and an outer diameter of about 0.03 to 0.170inches, section 69 of the container has an inner diameter of about 0.180to inches, and section 68 has a diameter of about 0.045 to about 0.190inches. In a particularly preferred embodiments piercer 26 has an innerdiameter of about 0.045 inches and an outer diameter of about 0.062inches and the section 68 of container 60 has an inner diameter of about0.070 inches and section 69 has an inner diameter of about 0.080 inches.

In embodiments of the present invention which include a second piercer52, such as those shown in FIGS. 2, 6 and 8, the second piercer 52 isalso preferably sharpened at the piercing end to about a 30° to 45°angle and the rim opposite the apex of the point is typically blunted.The inner diameter of piercer 52 is typically about 10 to 15% greaterthan the inner diameter of piercer 26.

In the embodiment shown in FIGS. 2 and 6, leaf springs 50 and 51 arepreferably stainless steel and are about 0.005 to 0.015 inches, morepreferably about 0.010 to 0.012 inches. Molded plastic springs can alsobe used but the extra thickness of such springs may be undesirable.

The configuration and dimensions of containers for use in the inhalationdevices of the present invention are adapted to the particular device.For example, in embodiments wherein the piercer 26 is a needle, thecontainer is preferably cylindrical. In some embodiments, the diameterof the container 60 is constant throughout, e.g., as shown in FIG. 4. Inother embodiments, the container is provided with a first section 68 anda second section 69, narrower in diameter than section 68, as shown in,e.g., FIG. 5. In yet other embodiments of the present invention, e.g.,as shown in FIG. 8, section 68 of container 60 tapers outwardly. Thistaper allows a greater volume of finely divided material to be loadedwithin a given depth. For proper evacuation of the container 60, thetaper should not exceed an angle of about 10° to 15°.

In the embodiments shown in the figures, other than embodiments similarto the embodiment shown in FIG. 4, the inner diameter of section 68 ofthe container 60 is about 10 to 15% larger than the outer diameter ofneedle 26. In embodiments similar to that shown in FIG. 4, because thefinely divided material is transferred to the needle as it pierces thecontainer, the inner diameter of the container is only about 10 to 15%larger than the outer diameter of needle 26 to minimize any residue offinely divided material which may be left behind in the container.

The amount and fluidity of the finely divided material to be deliveredwill in large part determine the dimensions of the inhalation devices ofthe present invention. The devices of the present invention are capableof delivering amounts of finely divided material ranging from about 0.1to 25 milligrams.

The dimensions of containers of the finely divided material for use inthe present invention are also adapted for the particle size and amountof such material to be dispensed and, preferably, are large enough toprovide an empty space 65 above the surface of the finely dividedmaterial. See, e.g., FIG. 5. This space 65 allows the finely dividedmaterial 64 to remain loose, avoiding agglomeration in storage andcompaction from pressure as the needle 26 penetrates the container 60.In preferred embodiments, the container 60 is about half filled withfinely divided material 64.

The particle size of the finely divided material to be delivered alsoinfluences the dimensions of the devices of the present invention. Thedesired particle size is determined, in part, by the mode of delivery,i.e., orally or nasally. Generally in oral administration, the intent isto get the greatest possible portion of the dose of finely dividedmaterial into the lungs and to avoid impingement on the lining of thebuccal cavity. Whereas for nasal administration, it is desirable to havethe major portion of the powder dose deposited on the nasal mucosa andthe minimum amount carried to the lungs. A finer particle size andgreater flow of air through the device of the present invention is usedin oral delivery as compared with nasal delivery to accomplish thedesired end. It is believed that the minimum air flow that woulddischarge the powder fully would also minimize the amount of powdercarried to the lungs for nasal applications.

Containers for use in the present invention are sealed at one or bothends with a conventional piercable material, such as a plastic or metalfilm, using methods known to those skilled in the art. See, e.g., film61 in FIG. 5. In such embodiments, the thickness of the film is about0.002 to 0.004 inches. The desired characteristics for such sealingmaterials are high tensile strength to avoid tearing during perforationand resistance to the passage of moisture. In a preferred embodiment, apolyester film having heat activating adhesive on one side is used toseal the containers. Although polyester is preferred, other films knownin the art, such as aluminum foil, may also be employed. In onepreferred embodiment of the present invention wherein the container isremovably sealed, the removable seal comprises a hermetic foil sealwhich is provided with an integral tab for ease of manual removal.

In the manufacture of embodiments of the present invention whereinmultiple containers 60 are disposed in disk 70, the disk 70 is typicallyfirst sealed on one side with a piercable sealing material. The finelydivided material 64 to be dispensed is then added to the multiplecontainers 60 disposed in disk 70 and the containers 60 are thenhermetically sealed by sealing the other side of disk 70 either with aremovable seal or with piercable sealing material.

The devices and containers of the present invention are made fromconventional materials and by conventional techniques known to those ofordinary skill in the art. To ensure simple manufacture of such devicesand containers, it is advantageous to use a readily processable plasticwhere suitable.

It will be apparent to the skilled artisan in light of the teachings ofthe present invention that configurations of body member 20, holder 40,piercer 26 and/or and piercers 26, 52 other than those shown may beutilized without departing from the spirit and scope of the invention.

For example, holder 40 may be connected to the body member 20 at variousangles as illustrated in FIG. 9: FIG. 9A showing a 45° angle, FIGS. 9Band 9C a 90° angle, and FIG. 9D a 30° angle. In yet another embodimentshown in FIG. 8, body member 20, holder 40, and piercers 26 and 52 arearranged in parallel, i.e., at 0° angle. Furthermore, the embodimentshown in FIG. 8 is pocketable and less conspicuous in use, beingsomewhat pen-like in appearance.

In use, the cover 44 of the embodiment shown in FIG. 8 is removed, thesealed container 60 is inserted in the holder 40, and the bottom seal ofcontainer 60 is pierced. The cover 44 is replaced and pressed home topierce the top seal. After removing the dust cap 54, the user places themouthpiece 24 in the mouth and inhales. In preferred embodiments, thedimensions are as follows: overall length, about 3 to 6 inches;diameter, about 0.25 to 0.75 inches; length of body member 20, about 2to 4 inches; length of cover 44, about 1.5 to 2.5 inches; length ofpiercer 26, about 1 to 1.75 inches; and length of piercer 52, about0.375 to 0.75 inches. In one such preferred embodiment for oralinhalation the breath required for actuation of the device was onlyabout 25 liters per minute. The dimensions of this device were asfollows: overall length of about 3.375 inches; an inside diameter ofabout 0.32 inches at the widest section and 0.25 inches at the narrowestsection of the venturi; body member 20 length of about 2.25 inches;holder 40 length of about 0.375 inches; piercer 26 length of about 1.1inches; and piercer 52 length of about 0.5 inches.

In the adaptations of the embodiment shown in FIG. 8 for nasalinhalation, the internal diameter is reduced to restrict the air flowfor delivery. For example, the narrowest section of the venturi can bereduced to about 0.187 inches in diameter to restrict the air flow.Furthermore, end 24 of the body member 20 is adapted to fit the humannose, and in some such embodiments, is bent upward at a 30° angle forcomfort in use. Other than diameter, the basic dimensions are similar tothose given above.

As is amply illustrated by the various embodiments in accordance withthe present invention described herein, by following the teachings ofthe present invention one of ordinary skill in the art can vary thedisclosed devices in structure by utilizing ordinary skill in the art tomeet the demands of a particular finely divided material, particularuser and so forth.

In order to illustrate the delivery advantages of the inhalation devicesof the present invention, administration of cortisol tritiated (H³-cortisol) using an inhalation device similar to that shown in FIGS. 1and 3A was compared with conventional oral administration of H³-cortisol by testing the urine of recipients of the H³ -cortisol for itspresence.

Free, unmetabolized H³ -cortisol present in the urine reflects theamount of H³ -cortisol in circulation. By free cortisol is meantcortisol which has not been altered by the liver. It is known that whencortisol is ingested, a good portion is inactivated or metabolized inthe liver.

FIG. 10 shows that more free H³ -cortisol was excreted in a 24 hourperiod in the urine when the H³ cortisol was administered via aninhalation device of the present invention as compared with ingestion.FIG. 11 shows that inhaled cortisol is more directly available forexcretion in the urine at an earlier time than is ingested cortisol.These results give very powerful indirect evidence that the inhaledcortisol was not just swallowed but reached the alveolar epithelium and,thus, entered systemic circulation in a manner almost equivalent todelivery of H³ -cortisol intravenously. In contrast, the ingestedcortisol was metabolized rapidly by the liver, because it was absorbedby the gut into the portal circulation.

A device similar to that shown in FIGS. 1 and 3A was tested to determineits delivery accuracy.

A container similar to that shown in FIGS. 3A and 5 was filled withabout 3.24 mg of finely divided material and placed in the holder 40 ofa device similar to that shown in FIGS. 1 and 3A. It was not necessaryto provide the container with a removeable seal 62 because the finelydivided material was dispensed immediately after being placed in thecontainer. The method of discharge was by hand vacuum pump with a volumeapproximately equal to the human lung. A constant stroke was used indispensing to minimize variation. Immediately after dispensing, thecontainer was removed from the device and weighed again, and the residueof finely divided material determined. This process was repeatedthirty-five times. The container was virtually purged with eachdelivery, and the residue remaining was very constant and very small.Thus, very accurate dose delivery was achieved by the use of a device ofthe present invention.

This invention will be further understood with reference to thefollowing examples which are purely exemplary in nature and are notmeant to limit the scope of the invention.

EXAMPLE Example 1

Administration of Tritiated Cortisol

A device similar to that shown in FIGS. 1 and 3A was used in thisExample.

H³ -cortisol for inhalation and for oral ingestion was prepared asfollows: 100 mg of cortisol was weighed in a clean crucible. 200 mμ ofH³ -cortisol dissolved in ethanol was added to the powder, andthereafter, the ethanol was evaporated in a desiccator and the samplemixed well. The mixture of unlabelled and H³ -cortisol was ground with astainless steel spoon shaped spatula. 5 mg of this mixture was weighedon glassene paper and then placed in a vial containing 0.5 ml of waterand 5.0 ml of pico-fluor. Approximately 6,523,223 counts per minute/5 mgwas prepared, giving a specific activity for H³ -cortisol of 1,279,063counts/minute/mg.

10 mg of the H³ -cortisol was administered to one subject by use of aninhalation device of the present invention and to another subjectorally.

The paper and tools used for weighing, as well the inhalation devicewere washed with ethanol and the amounts of H³ -cortisol found were thenappropriately subtracted from the counts obtained from dose inhaled andingested.

Excretion of free, unmetabolized cortisol as tritium was counted afterextraction from the urine into dichloromethane, which was dried down andcounted. The measurement of free H³ -cortisol was carried out viaconventional radioimmunoassay procedures after preliminary purificationby thin layer chromatography.

FIG. 10 demonstrates that of the total counts per minute excreted, for a24 hour period the percent as free H³ -cortisol was approximately 25%for the inhaled dose and less than 5% for the ingested dose.

FIG. 11 shows counts per minute of free H³ -cortisol excreted over a 24hour period for both oral ingestion and inhalation of the same dose. Itcan be seen that there was an early rise in counts per minute of free H³-cortisol after inhalation which is not observed in the urine of anindividual after oral ingestion of the labeled cortisol.

These results indicate that the inhaled H³ -cortisol reached thealveolar epithelium and the systematic circulation, whereas the ingestedcortisol was metabolized rapidly because it was absorbed by the gut intothe portal circulation.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof that will be suggested to persons skilled in the artare to be included in the spirit and purview of this application and thescope of the approved claims.

What is claimed is:
 1. A device for the oral or nasal inhalation offinely divided material from a sealed container of finely dividedmaterials, the device comprising:(i) a body member having a longitudinalaxis and an air passageway along said longitudinal axis, a first end ofthe air passageway for insertion into the mouth of a user and a secondend of the air passageway for intake of air responsive to inhalation ofa user and wherein a venturi portion is located between the first andsecond ends; (ii) a holder connected to the body member in the vicinityof the venturi for receiving at least one sealed container of finelydivided material; (iii) a first piercer for piercing a sealed containerof finely divided material at the end thereof disposed adjacent the bodymember while a sealed container is in the holder, the first piercerextending from the body member and into the holder; (iv) a secondpiercer for piercing the container while in the holder, the secondpiercer being capable of extending into the interior of the holder andhaving an air passageway therethrough open to the interior of the holderand to the atmosphere; and (v) engaging means for causing the piercers,while a sealed container is in the holder, to pierce a sealed containerof finely divided material;whereby when the engaging means causes thefirst and second piercers to pierce a sealed container while in theholder to create an air passageway therethrough, air drawn through thefirst piercer, a pierced container, the second piercer, and thepassageway of the body member cooperate to cause finely divided materialdisposed in a pierced container to be dispensed therefrom.
 2. A devicein accordance with claim 1, further comprising a locating means forpositioning a sealed container to be pierced adjacent the first andsecond piercers while a sealed container is in a receptacle disposed inthe holder.
 3. A device in accordance with claim 1, wherein the firstpiercer is disposed at or adjacent the smallest diameter of the venturior the midpoint of the tube.
 4. A device in accordance with claim 1,wherein a sealed container to be pierced is cylindrical and a sectionextending above the first piercer while a sealed container is in theholder has an inner diameter of about 0.035 to 0.180 inches, the firstpiercer has an inner diameter of about 0.01 to 0.15 inches and an outerdiameter of about 0.03 to 0.170 inches, and the second piercer has aninner diameter about 10 to 15% greater than the inner diameter of thefirst piercer.
 5. A device in accordance with claim 1, wherein when asealed container to be pierced is disposed in the holder and theengaging means causes the first and second piercers to pierce a sealedcontainer, the first piercer extends into a sealed container for adistance sufficient to hold a pierced section of a sealed containeragainst the inner surface of a sealed container.
 6. A device inaccordance with claim 1, wherein the holder is adapted to receive a diskcomprising multiple sealed containers of finely divided material.
 7. Adevice in accordance with claim 1, wherein the air passageway of theventuri has a minor diameter of about 0.2 to 0.5 inches and a majordiameter of about 0.3 to 0.8 inches.
 8. A device for the oral or nasalinhalation of finely divided material from a sealed container of finelydivided materials, the device comprising:(i) a body member having alongitudinal axis and an air passageway along said longitudinal axis, afirst end of the air passageway for insertion into the mouth of a userand a second end of the air passageway for intake of air responsive toinhalation of a user and wherein a venturi portion is located betweenthe first and second ends; (ii) a holder connected to the body member inthe vicinity of the venturi portion for receiving at least one containerof finely divided material; and (iii) a single piercer for piercing of asealed container of finely divided materials responsive to the insertionof a sealed container into the holder, the piercer extending from thebody member and into the holder and having a passageway having an inneropening only slightly smaller than the inner diameter of a sealedcontainer;whereby when a removably sealed container is placed in theholder thereby causing the piercer to pierce a sealed container and asealed container is unsealed, air drawn through an unsealed and piercedcontainer, the piercer, and the body member cooperate to cause finelydivided material disposed in an unsealed container to be dispensedtherefrom.
 9. A device for the oral or nasal inhalation of finelydivided material from a sealed container which comprises:(i) a bodymember having a longitudinal axis and an air passageway along saidlongitudinal axis, a first end of the air passageway for insertion intothe mouth of a user and a second end of the air passageway for intake ofair responsive to inhalation of a user and wherein a venturi portion islocated between the first and second ends; (ii) a holder connected tothe body member in the vicinity of the venturi for receiving at leastone sealed container of finely divided material; and (iii) at least onepiercer for piercing through a sealed container while a sealed containeris in the holder, the piercer having a passageway therethrough open tothe body member and to the holder and extending from the body memberthrough the holder for a distance greater than the dimension of a sealedcontainer to be pierced;whereby when a sealed container is placed in theholder thereby causing the piercer to pierce through a sealed containerand the transfer of the finely divided material from a container to thepassageway of the piercer, air drawn through the piercer and the airpassageway of the body member cooperate to cause the finely dividedmaterial disposed in the piercer to be dispensed therefrom.
 10. Thedevice of claim 9, wherein the piercer is approximately cylindrical anda sealed container to be pierced has an inner diameter greater than theouter diameter of the piercer by about 10 to 20%.
 11. A device inaccordance with claims 8, 9, or 1, wherein the piercer comprises aneedle.
 12. A device in accordance with claim 11, wherein the needlemeans is sharpened at the piercing end to about a 30° to 45° angle andthe rim of the needle opposite the apex is blunted.
 13. A device inaccordance with claims 8, 9, or 1, wherein a sealed container to bepierced is a cylindrically shaped cartridge sealed at both ends andpartially filled with finely divided material.
 14. A device inaccordance with claims 8 or 1, wherein both a sealed container to bepierced and the piercer are cylindrical and the end of a sealedcontainer which is to be disposed adjacent the body member while in theholder, has a diameter about 0.005 to 0.015 inches greater than thediameter of the piercer extending from the body member.
 15. A device inaccordance with claim 14, wherein the diameter of the end of a sealedcontainer to be pierced which is to be disposed adjacent the body memberwhile in the holder, increases about 10 to 20% at a distance from saidend about equal to the diameter of the piercer extending from the bodymember.
 16. A device in accordance with claims 8, 9, or 1, wherein asealed container to be pierced is provided with up to about 25 mg offinely divided material.
 17. A device in accordance with claims 8, 9, or1, wherein a sealed container to be pierced is provided with about 0.5to 5 mg of finely divided material.
 18. A device in accordance withclaims 8, 9, or 1 wherein the holder has a longitudinal axis fromsubstantially perpendicular to at about a 45° angle to the longitudinalaxis of said body member.